CYP1A inhibitors: Recent progress, current challenges, and future perspectives

Abstract

Mammalian cytochrome P450 1A (CYP1A) are key phase I xenobiotic‐metabolizing enzymes that play a distinctive role in metabolic activation or metabolic clearance of a variety of procarcinogens, drugs, and endogenous substances. Human CYP1A subfamily contains two members (hCYP1A1 and hCYP1A2), which are known to catalyze the oxidative activation of some environmental procarcinogens into carcinogenic species. Increasing evidence has demonstrated that CYP1A inhibitor therapies are promising strategies for cancer chemoprevention or overcoming CYP1A‐associated drug toxicity and resistance. Herein, we reviewed recent advances in the discovery and characterization of hCYP1A inhibitors, from the discovery approaches to structural features and biomedical applications of hCYP1A inhibitors. The inhibition potentials, inhibition modes, and inhibition constants of all reported hCYP1A inhibitors are comprehensively summarized. Meanwhile, the structural features and structure–activity relationships of different classes of hCYP1A1 and hCYP1A2 inhibitors are analyzed and discussed in depth. Furthermore, the major challenges and future directions for this field are presented and highlighted. Collectively, the information and knowledge presented here will strongly facilitate the researchers to discover and develop more efficacious CYP1A inhibitors for specific purposes, such as chemo‐preventive agents or as tool molecules in hCYP1A–related fundamental studies.

Natural compound screening predicts novel GSK-3 isoform-specific inhibitors

“…As a result, these drugs are less likely to be pumped out of the cell by the glycoprotein. CYP1A2 is a member of the cytochrome P450 superfamily of enzymes that catalyzes many reactions involved in drug metabolism and oxidizes the organic molecules to eliminate them from circulation [45]. In the present study, Catechin, Crocetin, Rosmarinic acid, Resveratrol, Sesamin, Withaferin A, Costunolide, Serpentine, and Azithromycin were predicted not to inhibit CYP1A2, thus making them more likely to be metabolized by enzymes (Suppl.…”

Many human pharmaceuticals are weak inhibitors of the cytochrome P450 system in rainbow trout (Oncorhynchus mykiss) liver S9 fractions

“…The first objective of this study was to evaluate the qualitative correlation between the substrate selectivities between human and rainbow trout CYP1A and CYP3A homologs. Human CYP1A favors planar, relatively small aromatic molecules ( Dong et al, 2012 ; Dai et al, 2024 ). None of the pharmaceuticals assessed in this study are categorically strong inhibitors (IC 50 < 1 µM) of human CYP1A activity, but weak or predicted CYP1A inhibition is associated with orphenadrine and desloratadine, respectively ( Table 1 ).…”

Halogen Regulation in Vinylene-Linked Covalent Organic Frameworks for Efficient Photocatalytic C–H Thiolation of Quinone Derivatives

“…Quinones are important chemicals in nature and are widely used in various therapeutic drugs, such as anticancer, antibacterial, antifungal, antiviral, and antimalarial, because of their various biological and pharmacological activities. − Naphthoquinone is a significant branch of quinones and is known for its various biological and pharmacological activities, which have been widely reported and studied. − In particular, the quinonyl aryl thioether is a kind of molecule with proven biological activity and has wonderful applications in the synthesis and design of valuable medicine. Currently, although various transition-metals-based catalysts were explored to mediate the thiolation of naphthoquinones, − some drawbacks, including high cost, high toxicity, and environmental pollution, have further restricted their development.…”